When two genes are perturbed simultaneously, a surprising phenotype often emerges. Genetic interaction - defined by this phenomenon - suggests that the interacting genes have related functions. Here we propose to develop a new technology ("bar-code fusion genetics" or BFG) for detecting genetic interactions in S. cerevisiae. The BFG method exploits existing libraries of strains carrying bar-coded gene deletions, and harnesses the throughput and economy of next-generation sequencing technology. If successful, the BFG technology has the potential to allow a single technician in a single year to generate a map of genetic interactions amongst all 18 million S. cerevisiae gene pairs in any given growth condition. In the context of this two-year pilot proposal, we propose to develop and optimize the BFG technology, and assess its sensitivity and potential value by applying it to the processes of DNA repair and RNA polymerase II transcription elongation. Two genes are defined to have a genetic interaction if the perturbation of both genes together yields a surprising phenotype. Complex human diseases such as cancer or diabetes require multiple mutations and are therefore the results of genetic interaction. Here we propose a technology in the model organism S. cerevisiae that could economically map genetic interactions amongst all genes in a given growth environment, and apply the approach in a pilot study of DNA repair and transcription genes.